| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or advanced colorectal cancer (mCRC) with acquired resistance to chemotherapy |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer in the colon or rectal area, which has spread to other parts of the body and which is no longer sensitive to chemotherapy |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To determine the safety and toxicity profile of SCO-101 in combination with FOLFIRI
2. Stage 1 and 3: Maximum tolerated dose (MTD) of SCO-101 in combination with FOLFIRI as evaluated by CTCAE v. 5.0
3. Stage 2: To assess the Objective Response Rate (ORR) according to RECIST 1.1 criteria after 20 weeks from treatment start.
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| E.2.2 | Secondary objectives of the trial |
1. To assess the CBR, PFS, OS, and ORR
2. To assess the DOR in patients with an objective response, and DOR compared to DOR of initial FOLFIRI treatment (without SCO-101)
3. To establish the PK profile of SCO-101
o SCO-101 in combination with FOLFIRI, and
o Irinotecan, SN-38 and SN-38-glucuronide
o 5-FU
4. To evaluate clinical biomarkers to predict response to SCO-101 treatment in combination with FOLFIRI. The following biomarkers will be evaluated:
o In all stages:
Total, unconjugated and conjugated bilirubin,
UGT1A1 polymorphism
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability to understand and willingness to provide written informed consent before any trial-related activities.
2. Age 18 years or older.
3. Histologically verified colorectal adenocarcinoma;
4. Non resectable mCRC in patients:
A. Stage 1: with or without BRAF, KRAS or repair enzyme mutations.
B. Stage 2: without BRAF, KRAS or known repair enzyme mutations
C. Stage 3: with or without BRAF, RAS or repair enzyme mutations, actual status to be confirmed prior to enrollment
5. Previous treatment and documented progressive disease with irinotecan and 5-FU (including 5-FU based analogs, e.g. capecitabine) based chemotherapy regimens (with or without antiangiogenetic and EGFR inhibitory biological treatment)
6. Maximum reduction of 33% in prior dose of FOLFIRI
7. Previous treatment with an oxaliplatin-containing treatment regimen and no indication for re-challenge with oxaliplatin. The patient can received oxaliplatin treatment before and/or after treatment with FOLFIRI.
8. A. Stage 1 and 3 only: Evaluable disease by CT scan or MRI
B. Stage 2 only: Measurable disease by CT scan or MRI, according to RECIST
9. Performance status of ECOG ≤ 1.
10. Recovered to Grade 1 or less from prior surgery or acute toxicities of prior radiotherapy or treatment with cytotoxic or biologic agents.
11. ≥ 2 weeks must have elapsed since any prior surgery
12. Adequate conditions as evidenced by the following clinical laboratory values:
•Absolute neutrophils count (ANC) ≥ 1.5 x 10^9/L
• Haemoglobin is at least 6,0 mmol/L
• Platelets ≥ 100 x 10^9 /L
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN
• Total serum bilirubin ≤ 1.0 ULN
• Alkaline phosphatase ≤ 2.5 x ULN
• Creatinine ≤ 1.5 ULN
• Normal kidney function defined by the centers with the method usually employed locally i.e. either creatinine (≤ 1.5 ULN) or calculated creatinine clearance or eGFR within normal limits determined according to local standards.
• Adequate blood clotting function as defined by the International Normalized Ratio (INR) ≤ 1.5
13. Life expectancy equal to or longer than 3 months.
14. Sexually active males and females of child-producing potential must use adequate highly effective contraception during the trial and for at least 6 months after the last dose of study drug. Moreover, monthly pregnancy testing will be done during the treatment phase of the trial. (Highly effective contraceptive measures are methods that can achieve a failure rate of less than 1% per year. These include: intrauterine devices, hormonal contraceptives associated with inhibition of ovulation (oral, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release). A vasectomised partner or sexual abstinence may be regarded as highly effective methods, if this is the usual and preferred lifestyle of the subject. Sterilised or infertile subjects are exempt from the requirement to use contraception. In order to be considered sterile or infertile, subjects must generally have undergone surgical sterilisation (vasectomy/bilateral salpingectomy, hysterectomy and bilateral oophorectomy) or be postmenopausal defined as 12 months or more with no menses prior to enrolment. Double-barrier methods (condom+cervical cap with spermicide) are not considered highly effective)
15. Signed informed consent.
16. Patients are only eligible for inclusion if no further on label treatment alternatives are available, i.e:
a. They have progressed on all available standard treatments, and/or
b. are intolerant of all remaining standard treatments, and/or
c. decline treatment with all other standard treatments, and/or
d. if the patient from the treating doctors medical view cannot be offered further standard treatment for their cancer disease.
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| E.4 | Principal exclusion criteria |
1. Concurrent chemotherapy, radiotherapy, or other investigational drugs during study period.
2. Malabsorption syndrome or previous surgeries with resection of the stomach or small intestine, whereby absorption of SCO-101 may be affected. This includes patients with ileostomy.
3. Difficulty in swallowing tablets.
4. Clinical symptoms of CNS metastases requiring steroids.
5. Any active infection requiring parenteral or oral antibiotic treatment.
6. Known HIV positivity.
7. Known active hepatitis B or C.
8. Clinical significant (i.e. active) cardiovascular disease:
• Stroke within ≤ 6 months prior to day 1
• Transient ischemic attach (TIA) within ≤ 6 months prior to day 1
• Myocardial infarction within ≤ 6 months prior to day 1
• Unstable angina
• New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF)
• Serious cardiac arrhythmia requiring medication
9. Mental status is not fit for clinical study or CNS disease including symptomatic epilepsy.
10. Other medications or conditions that in the Investigator’s opinion would contraindicate study participation of safety reasons or interfere with the interpretation of study results. Other severe medical conditions, including serious heart disease, unstable diabetes, uncontrolled hypercalcaemia, clinically active infections or previous organ transplants. Participation in another clinical trial with experimental medication within 30 days prior to registration.
11. Known hypersensitivity to SCO-101, irinotecan, 5FU or structurally similar drugs (e.g. capecitabine), leucovorin and G-CSF.
12. Pregnant women or women who are breastfeeding.
13. Patients with known Dihydropyrimidine dehydrogenase (DPD) deficiency
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Safety and tolerability by assessing the number, frequency, and severity of adverse events (AEs) collected from the time of first treatment until four weeks after last administration of study treatment to evaluate safety of SCO-101 in combination with FOLFIRI determined according to CTCAE version 5.0
2. Stage 1 and 3: Maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) of SCO-101 in combination with FOLFIRI
3. Stages 2: Objective response rate (ORR) defined as CR and PR using the RECIST v. 1.1 after 20 weeks from treatment start.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| According to the protocol |
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| E.5.2 | Secondary end point(s) |
1. Progression free survival (PFS) defined as time in months from the date of first study treatment to the date of disease progression or death from any cause, whichever comes first;
2. Duration of response (DOR) (from first response to progression);
3. Duration of response (DOR) after administration of SCO-101 compared to DOR from patients' initial FOLFIRI treatment regimen (i.e. without SCO-101).
4. Overall survival (OS) defined as time in months from the date of first study treatment to the date of death;
5. ORR defined as CR and PR using the RECIST v. 1.1 for the entire treatment period
6. Clinical benefit rate (CBR) defined as the number of patients obtaining CR, PR, or SD ≥ 16 weeks according to RECIST v.1.1.
7. Pharmacokinetic profiles of SCO-101, Irinotecan, and SN-38, SN-38-glururonide and 5 FU, will be determined by means of: Time to maximum drug plasma concentration (tmax), Half-life (T½), Volume of Distribution (Vd/F), Clearance (CL/F), Area Under the plasma drug Concentration-time curve (AUC) and Maximum drug plasma concentration (Cmax).
8. Biomarker evaluation:
o Changes in levels of total, unconjugated and conjugated bilirubin in blood, from baseline (i.e., prior first dose of SCO-101), at each cycle, and until end of treatment; and correlation between patient tolerability and pharmacokinetic parameters for SCO-101 and FOLFIRI components.
o Selected UGT1A1 polymorphism (from a pre-treatment blood sample). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| According to the protocol |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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6 months after last patient´s last visit according to the study protocol, last patient
withdrawn informed consent, lost to follow-up, or death, whichever occurs first. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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